Positive pressure ventilation causes increases and fluctuations in cerebral venous pressure. Preliminary studies suggest that pressure ventilation selectively disrupts the blood-brain barrier in newborn pigs. Furthermore, it is when positive pressure ventilation is added to clinically common stress situations, such as respiratory failure, that effects on the cerebral circulation and blood-brain barrier may be accentuated. The proposed research addresses the hypothesis that positive pressure ventilation alters cerebral hemodynamics and increases blood-brain barrier permeability in newborns with respiratory failure and that arachidonic acid metabolites partly mediate these alterations. The specific aims are: 1) Determine the effects of positive pressure ventilation upon cerebral hemodynamics and blood-brain barrier function of healthy and compromised newborns; 2) Evaluate the contribution of positive pressure ventilation-induced increases in arachidonic acid metabolism to cerebral hemodynamics, cerebral microvascular reactivity, and blood-brain barrier function. 3) Determine if other systems activated by positive pressure ventilation can increase CSF prostanoids thus influencing cerebral hemodynamics and blood-brain barrier function. These experiments will use methods to study cerebral blood flow distribution (microspheres) and direct observation of the cerebral microcirculation (closed cranial window). We also will employ these analytical methods: a) radiolabeled tracers to examine blood-brain barrier function; b) superoxide dismutase inhibitable nitre-blue tetrazolium reduction for the detection of superoxide anion radical; c) radioimmunoassay for arachidonic acid metabolites, vasopressin and angiotensin. The experimental design includes conditions (hypercapnia, hypoxia, and hypotension) which often accompany respiratory failure in newborn humans. Presently all infants with respiratory failure are treated with positive pressure ventilation which makes the cerebral hemodynamic effects of pressure ventilation of clinical importance.